Our long-term goal is to test the hypothesis that endogenous systems counteract the adverse actions of alcohol and prevent or delay the development of alcohol addiction. We further hypothesize that malfunction of such pathways increases susceptibility for the development of alcoholism. This hypothesis is based on our recent studies demonstrating a homeostatic brain-derived neurotrophic factor (BDNF)-mediated signaling pathway that is upregulated by acute and intermittent exposure to moderate concentrations of ethanol, both in slices and in vivo, and suppresses sensitivity of mice to ethanol [3, 8]. For example, we observed that voluntary ethanol consumption in mice increases the expression of BDNF specifically in the dorsal striatum, a brain region that controls habit learning, and global reduction of the BDNF gene or inhibition of the BDNF pathway increases ethanol-drinking behaviors [3, 8]. Using a combination of molecular and behavioral approaches, we plan to: 1) Determine whether endogenous dorsal striatal BDNF and its downstream effectors, the dopamine D3 receptor and the neuropeptide, dynorphin, are part of a regulatory mechanism controlling motivation to consume ethanol in rats. 2) Test whether a single nucleotide polymorphism in the BDNF gene that has been shown to impair BDNF function, and is linked to increased risk for various psychiatric disorders and addiction in humans, leads to a breakdown of this protective pathway in the dorsal striatum, and increases sensitivity of mice to the adverse actions of ethanol. 3) Determine whether chronic exposure to excessive levels of ethanol is associated with the inhibition of the BDNF pathway ex vivo and in vivo. Alcoholism is a devastating disease that manifests itself as uncontrolled drinking. Understanding the molecular mechanisms that control this phenotype are therefore of great interest and will likely lead to the identification of new targets for medication development to treat alcoholism, and may lead to the identification of genetic risk factors for the disease. This proposal is aimed to determine whether BDNF and its down-stream effectors, the dopamine D3 receptor and the neuropeptide Dynorphin, are part of an endogenous anti-addiction cascade. Our hypothesis further suggests that behavioral adaptations that result in addictive phenotypes, such as compulsive alcohol consumption, occur when this protective pathway is down-regulated, and/or when the BDNF gene is mutated. Alcohol dependence is a widespread problem in our society, and despite decades of research, very few medications exist to treat the disease. Results generated from this study could lead to the identification of new targets for medication development to treat alcoholism and to the identification of genetic risk factors for the disease.